Preparation of antithrombogenic polymeric materials

Abstract

Antithrombogenic polymeric materials are prepared by bonding a synthetic fibrinolytic compound or a combination of a synthetic fibrinolytic compound and a fibrinolytic enzyme to a polymeric material. Bonding is preferably by covalent or ionic bonding. The antithrombogenic polymeric materials are useful for preparing various types of medical articles that come into contact with blood.

What is claimed is: 
     
       1. A process for preparing an antithrombogenic polymeric material, which comprises treating a polymeric material selected from the group consisting of polyacrylic acid, polymaleic acid, polyglutamic acid, alginic acid, polyethyleneimine, polymethacryloyl chloride, a polymer of bisphenol A and epichlorohydrin, polyacrolein, polymaleic anhydride, a polyamide, poly(ethylene terephthalate), a polyurethane, a silicone rubber, polyethylene, polypropylene, polyvinyl chloride, polyvinyl alcohol, polyacrylonitrile, cellulose, cellulose acetate, poly(methylmethacrylate), a polyester elastomer, poly(vinylbenzyl trialkyl ammonium ion), poly(vinylbenzyl dialkyl sulfonium ion), poly(vinylbenzyl trialkyl phosphonium ion), poly(dialkyloctamethylene ammonium ion), poly(N,N-dialkyl-3,5-methylenepiperidinium ion), and poly(dialkylaminoethyl methacrylate), with a solution of a synthetic compound which contributes to dissolution of fibrin, said synthetic compound being selected from the group consisting of a 1,2-diphenylpyrazolidine derivative, an anthranilic acid derivative, a salicylic acid derivative, a cinnamic acid derivative, a β-aryl substituted aliphatic acid, and a carboxylic acid containing a heterocyclic ring thereby to cause the synthetic compound to bond covalently or ionically to the polymeric material. 
     
     
       2. A process for preparing an antithrombogenic polymeric material, which comprises treating a polymeric material having a reactive functional group capable of forming a covalent bond, said reactive functional group being selected from the group consisting of a carboxy group, an amino group, a chloroformyl group, a diazonium group, an azido group, an epoxy group, a formyl group, a bromoacetyl group, an isocyanato group, a carboxylic acid anhydride group, and an imidocarbonato group, with a solution of a synthetic compound which contributes to dissolution of fibrin said synthetic compound being selected from the group consisting of a 1,2-diphenylpyrazolidine derivative, an anthranilic acid derivative, a salicylic acid derivative, a cinnamic acid derivative, a β-aryl substituted aliphatic acid, and a carboxylic acid containing a heterocyclic ring thereby to bond the synthetic compound covalently to the polymeric material. 
     
     
       3. The process of claim 2, wherein the polymeric material having a reactive functional group capable of forming a covalent bond is polyacrylic acid, polymaleic acid, polyglutamic acid, alginic acid, polyethyleneimine, polymethacryloyl chloride, a polymer of bisphenol A and epichlorohydrin, polyacrolein, or polymaleic anhydride. 
     
     
       4. A process for preparing an antithrombogenic polymeric material, which comprises introducing a reactive functional group capable of forming a covalent bond into a polymeric material selected from the group consisting of a polyamide, poly(ethylene terephthalate), a polyurethane, a silicone rubber, polyethylene, polypropylene, polyvinyl chloride, polyvinyl alcohol, polyacrylonitrile, cellulose, cellulose acetate, poly(methylmethacrylate), and a polyester elastomer, and then treating the polymeric material with a solution of a synthetic compound which contributes to dissolution of fibrin said synthetic compound being selected from the group consisting of a 1,2-diphenylpyrazolidine derivative, an anthranilic acid derivative, a salicylic acid derivative, a cinnamic acid derivative a β-aryl substituted aliphatic acid, and a carboxylic acid containing a heterocyclic ring thereby to bond the synthetic compound covalently to the polymeric material. 
     
     
       5. The process of claim 4, wherein the reactive functional group capable of forming a covalent bond is a carboxy group, an amino group, a chloroformyl group, a diazonium group, an azido group, an epoxy group, a formyl group, a bromoacetyl group, an isocyanato group, a carboxylic acid anhydride group, or an imidocarbonato group. 
     
     
       6. A process for preparing an antithrombogenic polymeric material, which comprises treating a polymeric material having an anion exchange group selected from the group consisting of a primary amino group, a secondary amino group, a tertiary amino group, a quaternary ammonium group, a tertiary sulfonium group and a quaternary phosphonium group present at the terminals of, and/or on the side chains of, and/or on the main chains of the polymeric material with a solution of a synthetic compound which contributes to dissolution of fibrin and is capable of forming an anion, said synthetic compound being selected from the group consisting of a 1,2-diphenylpyrazolidine derivative, an anthranilic acid derivative, a salicyclic acid derivative, a cinnamic acid derivative, a β-aryl substituted aliphatic acid, and a carboxylic acid containing a heterocyclic ring thereby to bond the synthetic compound ionically to the polymeric material. 
     
     
       7. The process of claim 6, wherein the polymeric material having an anion exchange group is polyethyleneimine, poly(vinylbenzyl trialkyl ammonium ion), poly(vinylbenzyl dialkyl sulfonium ion), poly(vinylbenzyl trialkyl phosphonium ion), poly(dialkyloctamethylene ammonium ion), poly(N,N-dialkyl-3,5-methylenepiperidinium ion), or poly(dialkylaminoethyl methacrylate). 
     
     
       8. A process for preparing an antithrombogenic polymeric material, which comprises introducing a functional group containing an anion exchange group by chemical reaction into a polymeric material selected from the group consisting of a polyamide, poly(ethylene terephthalate), a polyurethane, a silicone rubber, polyethylene, polypropylene, polyvinyl chloride, polyvinyl alcohol, polyacrylonitrile, cellulose, cellulose acetate, poly(methyl methacrylate), and a polyester elastomer, and then treating the polymeric material with a solution of a synthetic compound which contributes to dissolution of fibrin and is capable of forming an anion, said synthetic compound being selected from the group consisting of a 1,2-diphenylpyrazolidine derivative, an anthranilic acid derivative, a salicylic acid derivative, a cinnamic acid derivative, a β-aryl substituted aliphatic acid, and a carboxylic acid containing a heterocyclic ring thereby to bond the synthetic compound ionically to the polymeric material. 
     
     
       9. The process of claim 8, wherein the anion exchange group is a primary amino group, a secondary amino group, a tertiary amino group, a quaternary ammonium group, a tertiary sulfonium group or a quaternary phosphnium group. 
     
     
       10. A process for preparing an antithrombogenic polymeric material, which comprises treating a polymeric material with a solution of a synthetic compound which contributes to dissolution of fibrin, said synthetic compound being selected from the group consisting of a 1,2-diphenylpyrazolidine derivative, an anthranilic acid derivative, a salicylic acid derivative, a cinnamic acid derivative, a β-aryl substituted aliphatic acid, and a carboxylic acid containing a heterocyclic ring, and with a solution of a fibrinolytic enzyme, thereby to cause a covalent bonding or ionic bonding of said synthetic compound and of the enzyme to the polymeric material. 
     
     
       11. The process of claim 10, wherein the enzyme is urokinase.